The observation that many forms of human neoplasia result from mutations in cellular homologs of viral oncogenes has led to the identification of a vast array of cellular genes capable of promoting cellular transformation. The nature of the genes responsible for transformation, and the role of these genes in normal and abnormal development, continues to be the principal goal of this Program Project. All of the individual proposals share a coherent theme: an examination of the function of protein tyrosine kinases in the setting of the whole animal to learn which tissues and cell types require specific tyrosine kinase activity, to discern their role in development, and to examine how alterations in their expression can lead to transformation. Each of these projects relies heavily on the generation of transgenic animals and recent advances in gene targeting to create mutant cell lines in virtually any gene for which a DNA sequence is available. The PI of project 8 has successfully created a mutation in the germline of mice at the c-abl locus, and has demonstrated that these mice are defective in B cell development. Experiments are described to characterize the nature of a B cell defect in further detail. The PI of project 10 has generated homozygous mutants in the receptor tyrosine kinase, c-ret, which exhibit defects in the development of the kidney as well as in the development of the peripheral nervous system. The PI of project 1 and his laboratory continue to examine the role of CD4, which associates with a cytoplasmic tyrosine kinase, in shaping the T cell repertoire during development, and the paradoxical role of CD4 as the receptor mediating efficient entry of the AIDS virus. Thus, this collaborative effort merges the conceptual and technical advances of molecular virology with recent advances in mammalian developmental genetics to examine the nature of the changes in protein tyrosine kinases responsible for malignant transformation, and for the role of these protooncogenes in normal development.